Osilodrostat
Osilodrostat is a newer oral cortisol-synthesis inhibitor approved for Cushing's disease. It potently inhibits 11-beta-hydroxylase (and, higher up, aldosterone synthase), normalising cortisol in the majority of patients in trials. Like metyrapone it lowers cortisol production rather than blocking the receptor, and diverts precursors toward androgens and mineralocorticoids, with attendant side effects. No physique use.
01 Overview
Osilodrostat inhibits CYP11B1 (11-beta-hydroxylase), the terminal enzyme of cortisol synthesis, and also CYP11B2 (aldosterone synthase). In the LINC pivotal trials the majority of Cushing's disease patients achieved normal urinary free cortisol. It is dosed twice daily and titrated to cortisol.
Because it blocks the pathway downstream, precursors accumulate: this raises adrenal androgens (hirsutism, acne) and mineralocorticoid precursors (hypertension, hypokalaemia, oedema), and over-suppression causes adrenal insufficiency. It also prolongs the QT interval. Its use is confined to endocrinology; there is no evidence base for cortisol-blockade as a recovery or physique aid.
02 Mechanism
Potent oral inhibitor of 11-beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), reducing cortisol (and aldosterone) synthesis.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| Cushing's (start) | 2 mg | Oral | Typical starting dose twice daily. |
| Cushing's (titrated) | 4–30 mg/day | Oral | Titrated twice-daily to normalise cortisol; max ~30 mg/day. |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| Normalisation of cortisolPotent, reliable reduction of cortisol in Cushing's disease. | majority of patients in trials | Clinical | |
| Improvement in cortisol-excess featuresAssociated improvements in blood pressure, weight and glucose as cortisol normalises. | trial-reported | Clinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| Adrenal insufficiencyHypocortisolism-related nausea, fatigue and hypotension from over-suppression. | Severe | Dose-dependent | Clinical | |
| Hypokalaemia / hypertension / oedemaAccumulation of mineralocorticoid precursors raises blood pressure and lowers potassium. | Moderate | Common | Clinical | |
| QT prolongationDose-dependent prolongation of the QT interval. | Moderate | Dose-related | Clinical | |
| Hirsutism / acneAndrogenic skin effects from raised adrenal androgen precursors. | Mild | Common in women | Clinical |